Controlled clinical trials investigating ongoing questions about extracorporeal membrane oxygenation (ECMO) for patients with the acute respiratory distress syndrome (ARDS), including what the optimal mechanical ventilation (MV) tidal volume (TV) strategies are and whether ECMO potentiates injurious host responses, are difficult. We therefore conducted a systematic literature search and review to characterize studies investigating ECMO in adult animal lung injury models and to determine whether they inform these questions. A systematic literature search with relevant search terms was conducted of four data bases through 2/2/24. Forty-five studies met inclusion criteria, and most parameters examined were represented similarly in studies with (n = 24) or without (n = 21) severe ARDS PaO2/FiO2s levels (≤ 100 mmHg or > 100 mmHg). Overall, while only 11 studies were published from 1971 to 2005, 5, 8, and 11 were published in subsequent 5-year periods up to 2020 and then 10 through 2/2/24 (Figure 1). Most studies investigated pig or sheep models (n = 32), but since 2016, six studies employed rat models. Eighteen studies administered lung lavage alone or with another lung injury challenge (17 with PaO2/FiO2s ≤ 100) and 9 used oleic acid. Although seven studies administered lipopolysaccharide, very different from clinical ARDS only one used a bacterial and none a viral challenge. Thirty-two studies employed V-V ECMO. The most frequent duration of ECMO investigated was 24 h in 16 studies but only 2 studies investigated longer periods (48 and 96 h). Differences in study questions, methodologies and outcome measures precluded formal meta-analysis. However, overall in studies that compared mechanical ventilation alone (MV) to ECMO groups or that compared differing ECMO groups: in 5 studies ECMO supported tidal volume reductions that approached apneic levels in 2; all but 1 of 10 studies indicated that ECMO with or without TV reductions either did not increase or reduced lung injury measures; 2 studies did while 4 did not find that ECMO aggravated molecular or cellular markers of inflammation; and only 2 studies examined host thrombotic responses with ECMO. Animal models to date have addressed important questions facing ECMO use for ARDS, but ones more closely simulating ARDS in patients appear warranted.

Disruption of nicotinamide adenine dinucleotide (NAD) biosynthesis and function during infection may impair host defenses and aggravate inflammatory and oxidative organ injury. Increasingly, studies are investigating whether niacin or NAD metabolite treatment is beneficial in infection and sepsis animal models. We examined whether this preclinical experience supports clinical trials. A systematic review of three data bases was conducted through 2/29/2024 and a meta-analysis was performed comparing niacin or NAD metabolite treatment to control in adult animal models employing microbial challenges. Fifty-six studies met inclusion criteria, with 24 published after 2019. Most studies employed mouse (n = 40 studies) or rat (n = 12) models and administered either a bacterial toxin (n = 28) or bacterial (n = 19) challenge. Four and three studies employed viral or fungal challenges respectively. Studies investigated an NAD metabolite alone (n = 44), niacin alone (n = 9), or both (n = 3), usually administered before or within 24h after challenge (n = 50). Only three and four studies included standard antimicrobial support or started treatment > 24h after challenge respectively. In similar patterns with differing animal types (p ≥ 0.06), compared to control across those studies investigating the parameter, niacin or NAD treatment decreased the odds ratio of mortality [95% confidence interval (CI)] [0.28 (0.17, 0.49)] and in blood or tissue increased antioxidant levels [standardized mean differences (95%CI)] (SMD) [3.61 (2.20,5.02)] and decreased levels of microbes [− 2.44 (− 3.34, − 1.55)], histologic and permeability organ injury scoring [− 1.62 (− 2.27, − 0.98) and − 1.31(− 1.77, − 0.86) respectively], levels of TNFα, IL-6 and IL-1β [− 2.47 (− 3.30, − 1.64), − 3.17 (− 4.74, − 1.60) and − 8.44 (− 12.4, − 4.5) respectively] and myeloperoxidase (MPO) [− 1.60 (− 2.06, − 1.14)], although with significant, primarily quantitative heterogeneity for each (I2 ≥ 53%, p < 0.01) except MPO. Treatment increased blood or tissue NAD+ levels and decreased chemical organ injury measures and oxidation markers but differently comparing species (p ≤ 0.05). Only 2 and 9 survival studies described power analyses or animal randomization respectively and no study described treatment or non-histologic outcome measure blinding. Among survival studies, Egger’s analysis (p = 0.002) suggested publication bias. While suggestive, published animal studies do not yet support clinical trials testing niacin and NAD metabolite treatment for infection and sepsis. Animal studies simulating clinical conditions and with randomized, blinded designs are needed to investigate this potentially promising therapeutic approach.

OBJECTIVES:To date, studies have not provided definitive answers regarding whether previous immune checkpoint inhibitor (ICI) treatment alters outcomes for cancer patients with COVID-19. METHODS:The OnCovid registry (NCT04393974) was searched from February 27, 2020, to January 31, 2022, for patients who received systemic anti-cancer therapy in the 4 weeks before laboratory-confirmed COVID-19 diagnosis. Propensity-score matching using country, vaccination status, primary tumor type, sex, age, comorbidity burden, tumor stage, and remission status investigated differences in predefined clinical outcomes comparing those who had or had not received ICIs. RESULTS:Of 3523 patients screened, 137 ICI-only and 1378 non-ICI met inclusion criteria. Before matching, ICI patients were older, male, enrolled at centers in Italy, and had histories of smoking, thoracic cancers, advanced cancer stages, and active malignancies (P ≤0.02). After matching, there were 120 ICI and 322 non-ICI patients. ICI patients had no differences (odds ratio: 95% CI) in presenting COVID-19 symptoms (0.69: 0.37-1.28), receipt of COVID-specific therapy (0.88: 0.54-1.41), 14-day (0.95: 0.56-1.61), or 28-day (0.79: 0.48-1.29) mortalities. However, ICI patients required less COVID-19-related hospitalization (0.37: 0.21-0.67) and oxygen therapy (0.51: 0.31-0.83) and developed fewer complications (0.57: 0.36-0.92). CONCLUSION:In this propensity-score matched analysis, previous ICI therapy did not worsen and potentially improved COVID-19 outcomes in patients with cancer.

BACKGROUND:Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants.METHODS/EXAMPLES:We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field.CONCLUSION:Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

IntroductionBecause prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). MethodsIn Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production.ResultsStudy 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. DiscussionIn Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

Extensive animal investigation informed clinical practice regarding the harmful effects of high fractional inspired oxygen concentrations (FiO2s > 0.60). Since questions persist whether lower but still supraphysiologic FiO2 ≤ 0.60 and > 0.21 (FiO2 ≤ 0.60/ > 0.21) are also harmful with inflammatory lung injury in patients, we performed a systematic review examining this question in animal models. Studies retrieved from systematic literature searches of three databases, that compared the effects of exposure to FiO2 ≤ 0.60/ > 0.21 vs. FiO2 = 0.21 for ≥ 24 h in adult in vivo animal models including an inflammatory challenge or not were analyzed. Survival, body weight and/or lung injury measures were included in meta-analysis if reported in ≥ 3 studies. More than 600 retrieved reports investigated only FiO2s > 0.60 and were not analyzed. Ten studies with an inflammatory challenge (6 infectious and 4 noninfectious) and 14 studies without, investigated FiO2s ≤ 0.60/ > 0.21 and were analyzed separately. In seven studies with an inflammatory challenge, compared to FiO2 = 0.21, FiO2 ≤ 0.60/ > 0.21 had consistent effects across animal types on the overall odds ratio of survival (95

Determining how prior immune checkpoint inhibitor (ICI) therapy influences outcomes in cancer patients presenting with COVID‐19 is essential for patient management but must account for confounding variables.

Rationale: While oxygen therapy is standard for patients with pneumonia, a potential for increased oxidant damage exists. Understanding how oxygen therapy impacts inflammatory lung injury with SARS-CoV-2 infection (COVID-19) and related viruses will inform patient management. We investigated the effects of fractional inspired oxygen concentrations (FiO2s) of 30 or 60% in a mouse hepatitis virus-1 (MHV-1) model of acute lung injury we developed in A/J mice. Methods: MHV-1, a ß-coronavirus like SARS-CoV-2, can be studied at Biosafety Level-2. Intratracheal installation of MHV-1 in our model produces inflammatory lung injury, progressive arterial desaturation, and lethality over 14d, similar to COVID-19. Using this model, we compared outcomes in animals exposed in sealed chambers to atmospheric FiO2s of 21, 30 or 60% beginning 2h after of MHV-1 challenge and continuing for up to 14d. In each of three experiments, MHV-1 challenged animals were randomized to receive FiO2s of 21, 30 or 60% (10 animals per FiO2 group per experiment, 90 animals total). In another experiment, 30 animals challenged with noninfected viral culture medium were randomized to the same three FiO2s. Animals were observed for up to 14d. Results: Compared to FiO2 21%, chambers with FiO2 30 and 60% had similar humidities and temperatures but slightly lower carbon dioxide levels (CO2, p≤0.05) but all chamber CO2s were in the range of 400-2000 ppm. Compared to animals surviving with FiO2 21% in each of the three experiments [#survivors/#total animals (%)] [1/10 (10%);5/10 (50%);4/10 (40%)], and their survival times (Figure-1), survival was reduced in respective experiments with FiO2 30% [1/10 (10%);2/10 (20%);0/10 (0%)] and FiO2 60% [0/10 (0%);0/10 (0%);0/10 (0%)]. Patterns of survival were similar comparing the three experiments for each FiO2 and when combined, there was a significant dose-related difference in survival across the three FiO2's (p<0.0001) (Figure-1). Compared to FiO2 21%, survival decreased with FiO2 30% (p=0.06) and more so with FiO2 60% (p<0.0001) (log-rank test with Dunnett-Hsu adjustment). All animals challenged with noninfected viral culture medium and exposed similarly to FiO2s 21, 30 or 60% (n=10 per group) survived except one 30% animal that died at 12d despite appearing well. Conclusions: FiO2s of 30 and 60% that are considered therapeutic and relatively safe clinically, markedly worsened survival in mice with MHV-1 pneumonia, a ß-coronavirus like SARS-CoV-2. These findings emphasize the need to better understand how oxygen therapy impacts the pathogenesis of SARS-CoV-2 in patients.

BACKGROUND:Anthrax is a toxin-mediated zoonotic disease caused by Bacillus anthracis, with a worldwide distribution recognized for millennia. Bacillus anthracis is considered a potential biowarfare agent.METHODS:We completed a systematic review for clinical and demographic characteristics of adults and children hospitalized with anthrax (cutaneous, inhalation, ingestion, injection [from contaminated heroin], primary meningitis) abstracted from published case reports, case series, and line lists in English from 1880 through 2018, assessing treatment impact by type and severity of disease. We analyzed geographic distribution, route of infection, exposure to anthrax, and incubation period.RESULTS:Data on 764 adults and 167 children were reviewed. Most cases reported for 1880 through 1915 were from Europe; those for 1916 through 1950 were from North America; and from 1951 on, cases were from Asia. Cutaneous was the most common form of anthrax for all populations. Since 1960, adult anthrax mortality has ranged from 31% for cutaneous to 90% for primary meningitis. Median incubation periods ranged from 1 day (interquartile range [IQR], 0-4) for injection to 7 days (IQR, 4-9) for inhalation anthrax. Most patients with inhalation anthrax developed pleural effusions and more than half with ingestion anthrax developed ascites. Treatment and critical care advances have improved survival for those with systemic symptoms, from approximately 30% in those untreated to approximately 70% in those receiving antimicrobials or antiserum/antitoxin.CONCLUSIONS:This review provides an improved evidence base for both clinical care of individual anthrax patients and public health planning for wide-area aerosol releases of B. anthracis spores.

SummaryChloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non‐SARS‐CoV2 infection supported the use of these agents in the present SARS‐CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non‐SARS‐CoV2 viral infections do not support these agents' use for the SARS‐CoV2 outbreak.

Background. Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia. Methods. Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (IID)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production. Results. LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance. Conclusions. Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.

Anti-toxin agents for severe B. anthracis infection will only be effective if they add to the benefit of the two mainstays of septic shock management, antibiotic therapy and titrated hemodynamic support. Both of these standard therapies could negate benefits related to anti-toxin treatment. At present, three anthrax anti-toxin antibody preparations have received US Food and Drug Administration (FDA) approval: Raxibacumab, Anthrax Immune Globulin Intravenous (AIGIV) and ETI-204. Each agent is directed at the protective antigen component of lethal and edema toxin. All three agents were compared to placebo in antibiotic-treated animal models of live B. anthracis infection, and Raxibacumab and AIGIV were compared to placebo when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock. However, only AIG has actually been administered to a group of infected patients, and this experience was not controlled and offers little insight into the efficacy of the agents. To provide a broader view of the potential effectiveness of these agents, this review examines the controlled preclinical experience either in antibiotic-treated B. anthracis models or in titrated hemodynamic-supported toxin-challenged canines. The strength and weaknesses of these preclinical experiences are discussed.

Background. Clinical studies suggest obesity paradoxically increases survival during bacterial infection and sepsis but decreases it with influenza, but these studies are observational. By contrast, animal studies of obesity in infection can prospectively compare obese versus nonobese controls. We performed a systematic review and meta-analysis of animal investigations to further examine obesity’s survival effect in infection and sepsis. Methods. Databases were searched for studies comparing survival in obese versus nonobese animals following bacteria, lipopolysaccharide, or influenza virus challenges. Results. Twenty-one studies (761 obese and 603 control animals) met the inclusion criteria. Obesity reduced survival in 19 studies (11 significantly) and the odds ratio (95% CI) of survival (0.21(0.13, 0.35); I2 = 64%, p<0.01p < 0.01) but with high heterogeneity. Obesity reduced survival (1) consistently in both single-strain bacteria- and lipopolysaccharide-challenged studies (n = 6 studies, 0.21(0.13, 0.34); I2 = 31%, p=0.20 and n = 5, 0.22(0.13, 0.36); I2 = 0%, p=0.59, respectively), (2) not significantly with cecal ligation and puncture (n = 4, 0.72(0.08, 6.23); I2 = 75%, p<0.01), and (3) significantly with influenza but with high heterogeneity (n = 6, 0.12(0.04, 0.34); I2 = 73%, p<0.01). Obesity’s survival effects did not differ significantly comparing the four challenge types (p=0.49). Animal models did not include antimicrobials or glycemic control and study quality was low. Conclusions. Preclinical and clinical studies together emphasize the need for prospective studies in patients accurately assessing obesity’s impact on survival during severe infection.

In 2015, the Centers for Medicare and Medicaid Services (CMS) instituted an all-or-none sepsis performance measure bundle (SEP-1) to promote high-quality, cost-effective care. Systematic reviews demonstrated only low-quality evidence supporting most of SEP-1's interventions. CMS has removed some but not all of these unproven components. The current SEP-1 version requires patients with suspected sepsis have a lactate level, blood cultures, broad-spectrum antibiotics and, if hypotensive, a fixed 30 mL/kg fluid infusion within 3 hours, and a repeat lactate if initially elevated within 6 hours. Experts have continued to raise concerns that SEP-1 remains overly prescriptive, lacks a sound scientific basis and presents risks (overuse of antibiotics and inappropriate fluids not titrated to need). To incentivize compliance with SEP-1, CMS now publicly publishes how often hospitals complete all interventions in individual patients. However, compliance measured across hospitals (5 studies, 48-2,851 hospitals) or patients (three studies, 110-851 patients) has been low (approximately 50%) which is not surprising given SEP-1's lack of scientific basis. The largest observational study (1,738 patients) reporting survival rates employing SEP-1 found they were not significantly improved with the measure (P=0.53) as did the next largest study (851 patients, adjusted survival odds ratio 1.36, 95% CI, 0.85 to 2.18). Two smaller observational studies (158 and 450 patients) reported SEP-1 improved unadjusted survival (P≤0.05) but were confounded either by baseline imbalances or by simultaneous introduction of a code sepsis protocol to improve compliance. Regardless, retrospective studies have well known biases related to non-randomized designs, uncontrolled data collection and failure to adjust for unrecognized influential variables. Such low-quality science should not be the basis for a national mandate compelling care for a rapidly lethal disease with a high mortality rate. Instead, SEP-1 should be based on high quality reproducible evidence from randomized controlled trials (RCT) demonstrating its benefit and thereby safety. Otherwise we risk not only doing harm but standardizing it.

Abstract Background Lethal B. anthracis infection produces high proinflammatory peptidoglycan (PGN) burdens in hosts. We investigated whether the lethality and inflammation anthrax PGN can produce are related. Methods At 6 h before and the start of 24 h anthrax PGN infusions, rats (n = 198) were treated with diluent (controls) or one of three IV-doses of either hydrocortisone (125, 12.5 or 1.25 mg/kg) or TNF-soluble receptor (TNFsr; 2000, 1000 or 333 μg/kg), non-selective and selective anti-inflammatory agents, respectively. Results Compared to controls, hydrocortisone 125 and 12.5 mg/kg each decreased 7-day lethality (p ≤ 0.004). Hydrocortisone 125 mg/kg decreased IL-1β, IL-6, TNFα, MCP, MIP-1α, MIP-2, RANTES and nitric oxide (NO) blood levels at 4 and 24 h after starting PGN (except MCP at 24 h). Each decrease was significant at 4 h (except MIP-1α that was significant at 24 h) (p ≤ 0.05). Similarly, hydrocortisone 12.5 mg/kg decreased each measure at 4, 24 and 48 h (except TNFα at 24 h and MIP-1α at 24 and 48 h and NO at 48 h). Decreases were significant for IL-6 and NO at 4 h and RANTES at 48 h (p ≤ 0.05). Hydrocortisone 1.25 mg/kg had non-significant effects. Each TNFsr dose decreased lethality but non-significantly. However, when doses were analyzed together, TNFsr decreased lethality in a potential trend (p = 0.16) and IL-6 and NO significantly at 4 h (p = 0.05). Conclusions Peptidoglycan-stimulated host inflammation may contribute to B. anthracis lethality.

Background Animal studies reporting immune checkpoint inhibitors (CPIs) improved host defense and survival during bacterial sepsis provided one basis for phase I CPI sepsis trials. We performed a systematic review and meta-analysis examining the benefit of CPI therapy in preclinical studies, and whether variables potentially altering this clinical benefit were investigated. Studies were analyzed that compared survival following bacteria or lipopolysaccharide challenge in animals treated with inhibitors to programmed death-1 (PD-1), PD-ligand1 (PD-L1), cytotoxic T lymphocyte-associated protein-4 (CTLA-4), or B- and T-lymphocyte attenuator (BTLA) versus control. Results Nineteen experiments from 11 studies ( n = 709) were included. All experiments were in mice, and 10 of the 19 were published from a single research group. Sample size calculations and randomization were not reported in any studies, and blinding procedures were reported in just 1. Across all 19 experiments, CPIs increased the odds ratio for survival (OR, 95% CI) [3.37(1. 55, 7.31)] but with heterogeneity ( I 2 = 59%, p < 0.01). After stratification by checkpoint molecule targeted, challenge site or type, or concurrent antibacterial treatment, CPIs had consistent effects over most experiments in the 9 that included antibacterial treatment [OR = 2.82 (1.60, 4.98), I 2 = 6%, p = 0.39 with versus 4.01 (0.89, 18.05), I 2 = 74%, p < 0.01 without]. All 9 antibiotic experiments employed cecal-ligation and puncture (CLP) bacterial challenge while 6 also included a Candida albicans challenge 3–4 days after CLP. In these six experiments ( n = 322), CPIs were directed at the fungal challenge when CLP lethality had resolved, and were consistently beneficial [2.91 (2.41, 3.50), I 2 = 0%, p = 0.99]. In the three experiments ( n = 66) providing antibiotics without fungal challenge, CPIs were administered within 1 day of CLP and had variable and non-significant effects [0.05 (0.00, 1.03); 7.86 (0.28, 217.11); and 8.50 (0.90, 80.03)]. No experiment examined pneumonia. Conclusions Preclinical studies showing that CPIs add benefit to antibiotic therapy for the common bacterial infections causing sepsis clinically are needed to support this therapeutic approach. Studies should be reproducible across multiple laboratories and include procedures to reduce the risk of bias.

Cortés-Puch, Irene MD; Applefeld, Willard N. MD; Wang, Jeffrey MD; Danner, Robert L. MD; Eichacker, Peter Q. MD; Natanson, Charles MD Author Information

Objectives: Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis. Data Sources: PubMed, EMBASE, Scopus, Web of Science, inception through October 2019. Study Selection: Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors. Data Extraction: Two investigators extracted data and evaluated study quality. Data Synthesis: Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly ( p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression. Conclusions: Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.

602 www.ccmjournal.org April 2020 • Volume 48 • Number 4 adjustment in modeling for illness acuity that was not available in the study by Martin et al (7) relying on administrative data, to better understand what, if any, effect ICU-level acuity may have on the observed variation in practice of direct discharge home. Similarly, an understanding of whether (and/or how much) the ICU organizational or intensivist coverage models were factors in practice variation would be important to further explore. Although prior work has suggested for selected patients, direct discharge home is safe, associated with shorter hospital stay, and does not pose increased hazard for rehospitalization, emergency department visit, or death (4), the study by Martin et al (7) does not describe whether there were differences in patient outcomes or health services use. The findings from this and other studies strongly suggest the practice of direct discharge home from ICU is likely to continue, if not grow. Further evaluation is urgently needed to reliably identify the ideal population, the optimal timing, and the appropriate care processes to safely transition patients direct from the ICU to home. We would, however, further submit this is also an opportunity for innovation and health systems improvement that may favorably impact patient flow and access to ICU services; reduce strained capacity; and shorten patient stays in hospital. Although for many patients “there’s no place like home”, their safety is primary, and we would strongly recommend that any ICU that has or anticipates directly discharging patients home from the ICU develop standardized procedures and protocols, educate patients, family caregivers, and healthcare professionals, and monitor outcomes. REFERENCES 1. Stelfox HT, Lane D, Boyd JM, et al: A scoping review of patient discharge from intensive care: Opportunities and tools to improve care. Chest 2015; 147:317–327 2. Jerath A, Austin PC, Wijeysundera DN: Days alive and out of hospital: Validation of a patient-centered outcome for perioperative medicine. Anesthesiology 2019; 131:84–93 3. Lau VI, Priestap FA, Lam JNH, et al: Factors associated with the increasing rates of discharges directly home from intensive care unitsA direct from ICU Sent Home Study. J Intensive Care Med 2018; 33:121–127 4. Stelfox HT, Soo A, Niven DJ, et al: Assessment of the safety of discharging select patients directly home from the intensive care unit: A Multicenter Population-Based Cohort Study. JAMA Intern Med 2018; 178:1390–1399 5. Huang YC, Huang SJ, Ko WJ: Going home to die from surgical intensive care units. Intensive Care Med 2009; 35:810–815 6. Lau VI, Lam JNH, Basmaji J, et al: Survival and safety outcomes of ICU patients discharged directly home-A direct from ICU Sent Home Study. Crit Care Med 2018; 46:900–906 7. Martin CM, Lam M, Allen B, et al: Determinants of Direct Discharge Home From Critical Care Units: A Population-Based Cohort Analysis. Crit Care Med 2020; 48:475–483 8. Lam JNH, Lau VI, Priestap FA, et al: Patient, family, and physician satisfaction with planning for direct discharge to home from intensive care units: Direct from ICU Sent Home Study. J Intensive Care Med 2020; 35:82–90 9. Bagshaw SM, Opgenorth D, Potestio M, et al: Healthcare provider perceptions of causes and consequences of ICU capacity strain in a large publicly funded integrated health region: A Qualitative Study. Crit Care Med 2017; 45:e347–e356 10. Senaratne MP, Irwin ME, Shaben S, et al: Feasibility of direct discharge from the coronary/intermediate care unit after acute myocardial infarction. J Am Coll Cardiol 1999; 33:1040–1046